P359: DOUBLE-HIT LEUKEMIA: A VERY HIGH-RISK SUBTYPE PH-LIKE ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: Zicong Huang, Ling Zhang, Xiaoyuan Gong, Jia LI, Shiyu Deng, Zihong Cai, Bingqing Tang, Kangyu Huang, Xin LI, Weihua Zhao, Ying Wang, Yang Xu, Qifa Liu, Suning Chen, Hongsheng Zhou
Journal: HemaSphere (2023)

Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a genetically and clinically heterogeneous disease. Inferior outcomes of Ph-like ALL remains a clinical challenge. In this study, we revealed synergistic prognostic effect arising from the activation of oncogenes and inactivation of the tumor suppressor gene (TSG) IKZF1 in Ph-like ALL. Aims: To determine the worst outcome subset in the high-dimension diversity of Ph-like ALL to provide guidance for a risk-directed strategy. Methods: This retrospective cohort study included 206 patients with of Ph-like ALL in six centers of South China Hematology Consortium (SCHC). We collected and analyzed the data of clinical characteristics, flow cytometry, fluorescence in situ hybridization (FISH), PCR, next-generation sequencing (NGS), RNA-seq and whole exome sequencing. The overall survival (OS) was investigated. Results: A total of 206 patients with Ph-like ALL were grouped as ABL-class fusions (44/206, 21.4%; ABL1, ABL2, CSF1R, PDGFRB), CRLF2 positive (52/206, 25.2%; rearrangement or high-expression), EPOR or JAK2 rearrangement (41/206, 19.9%), JAK-STAT pathway mutations (22/206, 10.7%; IL7R, SH2B3, JAK1, JAK3, FLT3), Ras pathway mutations only (17/206, 8.2%; KARS, NRAS, PTPN11, NF1), p-CRKL or pSTAT5 high-expression only (15/206, 7.3%) and Others (15/206, 7.3%) (Figure 1A). Patients with IKZF1 alternations were associated with inferior outcome compared with those without IKZF1 alternations (3-year OS: 53.5% and 72.9%, respectively, P=0.036, Figure 1B). To refine the subgroup with the worst outcome, 181 patients with available IKZF1 data were divided into four subgroups: (group A) either CRLF2 high-expression/rearrangement, EPOR/JAK2 rearrangement, or p-STAT5 high-expression together with IKZF1 alternations; (B) CRLF2/EPOR/JAK2/p-STAT5 only; (C) IKZF1 alternations only; and (D) Others. Results showed patients with combined CRLF2/EPOR/JAK2/p-STAT5 and IKZF1 alternations had worse outcomes compared with compared with the other three groups (A, B, C, and D, 3-year OS 35.1%, 73.4%, 71.9%, and 72.2%, respectively, P<0.001; Figure 3C). We defined group A as double-hit leukemia (DHL), and combined the remaining three groups into one group named non-DHL. Patients with DHL had the worst 3-year OS compared with non-DHL (35.1% and 72.7%, respectively, P<0.001; Figure 1D). Summary/Conclusion: This study suggests that DHL identifies patients with Ph-like ALL who have the worst outcomes and may guide the refinement of Ph-like ALL risk stratification for novel treatment strategies of "double-hit" targeting for both IKZF1 inactivation and oncogene activation.(This study was supported by National Natural Science Foundation of China (NSFC 82170163, 81970147, 81770170, to HSZ), the Science and Technology Planning Project of Guangdong Province (No. 2017A030313601 to HSZ), the Clinical Trial Funding of Southern Medical University (2016A020215112), and Nanfang Hospital (LC2016ZD009/2019CR012).)Keywords: Leukemia